Direct Muscle Delivery of GDNF With Human Mesenchymal Stem Cells Improves Motor Neuron Survival and Function in a Rat Model of Familial ALS

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease in which there is a progressive loss of motor neurons and their connections to muscle leading to paralysis. To maintain muscle connections in a rat model of familial ALS, we performed intramuscular transplantation with human mesenchymal stem cells (hMSC) as “Trojan horses” to deliver growth factors to the terminals of motor neurons as well as the skeletal muscles. hMSC engineered to secrete glial cell line derived neurotrophic factor (hMSC-GDNF) were transplanted bilaterally into three muscle groups. The cells survived within the muscle, released GDNF, and significantly increased the number of neuromuscular connections and motor neuron cell bodies in the spinal cord at mid stages of the disease. Furthermore, intramuscular transplantation with hMSC-GDNF could ameliorate motor neuron loss within the spinal cord which connected to the limb muscles with transplants. While disease onset was similar in all animals, hMSC-GDNF significantly delayed disease progression, increasing overall lifespan by up to 28 days, which is one of the longest effects on survival noted for this rat model of familial ALS. This pre-clinical data provides a novel and practical approach towards ex vivo gene therapy for ALS.

Current developments in gene therapy for amyotrophic lateral sclerosis

“…In this study, human MSCs (hMSC) isolated from neonatal bone marrow and transduced with LV encoding GDNF were transplanted into the skeletal muscle of a SOD1-G93A rat model. This work showed a neuroprotective effect, with an increase by 18 days in the lifespan, as well as a reduction in both degeneration of motor neurons in the spinal ventral horn and denervation of neuromuscular junctions [86]. The same research group reported in 2013 that the engineering of hMSCs to ectopically express both VEGF and GDNF could delay the onset of the disease by 6 days and more relevantly could prolong the lifespan of SOD1-G93A rats by 28 days, with the dual neurotrophic factors showing a synergistic effect in the maintenance of spinal motor neurons and neuromuscular junctions [84].…”

“…Some studies have reported the efficacy of using MSCs to overexpress different neurotrophic factors, which can be used as an ex-vivo gene therapy tool in ALS models [84,86,95]. A major milestone was reached in 2009 when Suzuki et al demonstrated the efficacy of this method [86]. In this study, human MSCs (hMSC) isolated from neonatal bone marrow and transduced with LV encoding GDNF were transplanted into the skeletal muscle of a SOD1-G93A rat model.…”

“…A number of neurotrophic factors have been proposed as being a promising avenue for gene therapy in light of their beneficial effects on animal models of ALS. Among the factors which have shown promise in facilitating neuroprotection in animal models are vascular endothelial growth factor (VEGF) [81][82][83][84], hepatocyte growth factor (HGF) [85], glial-derived neurotrophic factor (GDNF) [84,86,87], insulin-like growth factor 1 (IGF-1) [88][89][90] and granulocyte-colony stimulating factor (G-CSF) [91,92]. The delivery of these neurotrophic factors can be carried out by using different approaches, with emerging viral vector-based and cell-based therapies among some of the most promising techniques.…”

Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis

“…Benefits in survival are also noted when cells modified to secrete GDNF are injected in mutant SOD1 rodent models. Interestingly, implantation of human MSCs engineered to secrete GDNF into skeletal n/a n/a n/a n/a muscle were also able to support MN survival in the spinal cord [39], with synergistic effects attributed to vascular endothelial growth factor (VEGF) production [101]. Therefore, the ability of surrounding non-neuronal cells in the spinal cord and at the neuromuscular junction appears to play an important role in ALS pathogenesis, and the properties of stem cells are thereby ideally suited to achieve the goal of modulating the MN microenvironment.…”

Point-Of-Care Stem Cell Therapy (POCST): Multisite transplantation of autologous bone marrow-derived mononuclear cells in 85 patients with Amyotrophic Lateral Sclerosis improves survival

“…The Stem cell therapies (SCT) have proven beneficial influence in all affected neural tissues leading to motoneurons regeneration [41][42][43][44], astrocytes replacement that slows motoneuron loss with a consequent survival increase [45], microglia regeneration [46,47] and growth factors secretion that promotes maintenance of motoneurons [48,49]. The effects seemed to be greater when the SCs delivery is intrathecal (IT) [50] or intramuscular (IM) [51].…”